Project Summary Neurodegenerative protein misfolding diseases, the most common of which is Alzheimer's disease (AD), exact devastating personal and economic tolls on society. CNS stem cell (CNS-SC) transplantation has been touted, justifiably, as a promising approach for treatment of Alzheimer's disease (AD) and other degenerative brain diseases either by replacing lost cells or as a vehicle for delivery of therapeutic agents. CNS-SC transplantation also may offer new approaches for dissecting disease processes and mechanisms. The broad aim of this pilot project is to assess and refine neurosphere transplantation as a tool to dissect pathogenic mechanisms and spread of tau pathology. Two paradigms will be explored: 1) transplantation of CNS-SC containing neurospheres from mice that do not develop disease into disease models, and 2) transplantation of neurospheres from disease models into mice that do not develop disease. The substrate for these pilot studies is the well-characterized rTg(tauP301L)4510 model for the tauopathy frontotemporal dementia (FTD). AD is characterized by extracellular Ass amyloid plaques and intracellular neurofibrillarly tangles (NFTs) composed of aggregated tau protein. Of the two, NFTs are more tightly associated with cognitive decline, neuron loss, and dementia than are plaques, arguing for the relevance of the FTD model for AD as well as other tauopathies. Evidence suggests that soluble extracellular forms of tau, rather than intracellular neurofibrillary tangles (NFTs), may be the triggers of neuronal dysfunction and cell death. Experiments will compare transplants of neurospheres from eGFP-expressing tau null and mouse tau-expressing mice into newborn rTg(tauP301) and rTg(tauwt) mice that express comparable levels of human mutant or wild type tau, and track cell survival, differentiation into neurons, and synapse formation by the progeny of the transplanted cells. In addition to addressing the question of whether endogenous tau expression is required for deleterious effects of extracellular tau aggregates, replacement of lost host neurons will be assessed. The project will address the questions of whether neurons from rTg(tauP301L) neurospheres develop tauopathy and whether spread of tauopathy is influenced by mismatching of tau primary structures in the transplant and the host. Refined methods and tools will be developed to facilitate application of stem cell transplantation to understanding disease mechanisms; these should prove valuable beyond this specific project.